Follicle stimulating hormone (FSH) is one of two pituitary hormones that affect the testes and ovaries. The other is luteinizing hormone (LH). Together FSH and LH stimulate the production of estrogen and progesterone in women, and testosterone in men.
In men, FSH stimulates the production of sperm. Conversely, suppression of FSH production in men leads to a reduction in the production of sperm. As a result, substances that suppress FSH production in men have great potential as male fertility regulating agents. Unfortunately, many of the male fertility regulating agents currently being tested affect both FSH and LH simultaneously, thus sometimes producing undesired impotency as well as the desired infertility.
Inhibins are gonadal peptides that inhibit the release of FSH from the anterior pituitary. The existence of such inhibins was theorized more than 50 years ago when their role was thought to be feedback messengers from the gonads to the pituitary. In this regard it was postulated that the inhibins signal the pituitary gland that it has produced enough follicle stimulating hormone (FSH). The pituitary responds to this information by shutting down production of FSH. See generally, Franchimont, et al. (1979).
Since the inhibins suppress the hormone that stimulates production of sperm, inhibins are likely to inhibit sperm production as well. In addition, the inhibins are likely to suppress sperm production without affecting the production of LH, which is responsible for maintaining sexual libido.
Although the existence of inhibins was postulated more than 50 years ago, isolation and characterization of these putative peptides is just now occurring. For example, the isolation and synthesis of an inhibin-like gonadal peptide (from human seminal plasma) having 31 amino acid residues was recently reported. See Ramasharma, et al. (1984) and Yamashiro, et al. (1984). We have now isolated two additional inhibin-like peptides with activity in suppressing FSH release in vitro. The primary structures of these two new peptides contain the amino acid sequence of the previously reported inhibin-like peptide (ILP).
The previously reported inhibin-like peptide, ILP, was the first human peptide to be isolated and sequenced that had inhibin activity. As a result we refer to ILP and ILP-related inhibins as "alpha" inhibins. Since ILP has 31 amino acids, it is being referred to herein as alpha-inhibin-31 (alpha-IB-31). Since our two new peptides are related to alpha-inhibin-31, and contain 52 and 92 amino acids, respectively, they are referred to herein as alpha-inhibin-52 (alpha-IB-52) and alpha-inhibin-92 (alpha-IB-92).
The amino acid structure of alpha-inhibin-52 was recently reported by Lilja and Jeppson (1985). In addition Sheth, et al. (1984) and Seidah, et al., (1984) recently reported isolation and the complete amino acid sequence of human seminal plasma beta-inhibin. This "beta" peptide consists of 94 amino acids with serine and isoleucine as NH.sub.2 --and COOH-terminal residues respectively. Beta-inhibin has 5 cystine and 2 tryptophan residues. As will be seen from the disclosure that follows, none of the novel inhibins of the present invention have any cystine or tryptophan residues. Thus it is obvious that the novel inhibins of the present invention are different from beta-inhibin. It is possible these various inhibin-like peptides are derived from a larger inhibin-like protein or inactive precursor molecule.